NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp) AND Charcot-Marie-Tooth disease, type I

Clinical significance:Pathogenic (Last evaluated: Aug 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001049422.2

Allele description [Variation Report for NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)]

NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)

Gene:
EGR2:early growth response 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q21.3
Genomic location:
Preferred name:
NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)
HGVS:
  • NC_000010.11:g.62813413G>A
  • NG_008936.2:g.111488C>T
  • NM_000399.5:c.1225C>TMANE SELECT
  • NM_001136177.3:c.1225C>T
  • NM_001136178.2:c.1225C>T
  • NM_001136179.3:c.1075C>T
  • NM_001321037.2:c.1075C>T
  • NP_000390.2:p.Arg409Trp
  • NP_001129649.1:p.Arg409Trp
  • NP_001129650.1:p.Arg409Trp
  • NP_001129651.1:p.Arg359Trp
  • NP_001307966.1:p.Arg359Trp
  • LRG_239t1:c.1225C>T
  • LRG_239:g.111488C>T
  • NC_000010.10:g.64573173G>A
  • NM_000399.3:c.1225C>T
  • P11161:p.Arg409Trp
Protein change:
R359W; ARG409TRP
Links:
UniProtKB: P11161#VAR_007738; OMIM: 129010.0002; dbSNP: rs104894159
NCBI 1000 Genomes Browser:
rs104894159
Molecular consequence:
  • NM_000399.5:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136177.3:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136178.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136179.3:c.1075C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321037.2:c.1075C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease, type I (CMT1)
Synonyms:
Charcot-Marie-Tooth Neuropathy Type 1; Hereditary Motor and Sensory Neuropathy 1; Charcot-Marie-Tooth, Type 1
Identifiers:
MONDO: MONDO:0019011; MedGen: C0751036

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001213471Invitaecriteria provided, single submitter
Pathogenic
(Aug 1, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.

Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR.

Nat Genet. 1998 Apr;18(4):382-4.

PubMed [citation]
PMID:
9537424

Widening the phenotypical spectrum of EGR2-related CMT: Unusual phenotype for R409W mutation.

Leonardi L, Garibaldi M, Fionda L, Vanoli F, Loreti S, Morino S, Antonini G.

Clin Neurophysiol. 2019 Jan;130(1):93-94. doi: 10.1016/j.clinph.2018.11.007. Epub 2018 Nov 22. No abstract available.

PubMed [citation]
PMID:
30481651
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001213471.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with tryptophan at codon 409 of the EGR2 protein (p.Arg409Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Charcot-Marie-Tooth disease (CMT) and to segregate with CMT in a family (PMID: 9537424, 30481651). ClinVar contains an entry for this variant (Variation ID: 16750). This variant has been reported to affect EGR2 protein function (PMID: 10369870, 26204789, 27013732). This variant disrupts the p.Arg409 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26204789, Invitae). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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